Effect of Luteolin and Apigenin on the Production of Il-31 and Il-33 in Lipopolysaccharides-Activated Microglia Cells and Their Mechanism of Action

Abstract

Microglia cells are resident cells of the central nervous system (CNS) charged with modulating inflammation in the CNS. Overstimulation of microglia cells continuously releases inflammatory mediators that contribute to neurodegenerative diseases. Apigenin and Luteolin are flavonoids with reported anti-inflammatory activities. However, their effects on IL-31 and IL-33 production in microglial cells are unknown. Here, we investigated the effects of apigenin and luteolin on the production of IL-31 and IL-33 by microglia cells. SIM-A9 microglial cells were pre-treated with apigenin or luteolin and stimulated with lipopolysaccharides to evaluate the production of IL-31 and IL-33. The study revealed that apigenin and luteolin inhibited the production of IL-31 and IL-33 at the gene and protein expressions and the secretion levels. Using potent inhibitors of MAPK, NF-κB, and STAT3 signaling pathways, we demonstrated that apigenin and luteolin's suppression of ERK and JNK contributed to the inhibition of IL-31 and IL-33 in the MAPK pathway. Luteolin's suppression of NF-κB and STAT3 also contributed to the inhibition of IL-31 and IL-33. Further analysis revealed that both compounds prevented nuclear translocation of activated NF-κB and STAT3, an act that subsequently prevented their DNA binding activities. Collectively, the study suggested that apigenin and luteolin's regulation of signaling pathways contributed to the inhibition of IL-31 and IL-33, thus suggesting its importance for the improvement of neurodegenerative diseases involving these two cytokines.

Phenolic and Non-Polar Fractions of the Extracts from Fruits, Leaves, and Twigs of Elaeagnus rhamnoides (L.) A. Nelson—The Implications for Human Barrier Cells

“…Their effect on cytokines/chemokines release, such as TNF-α, IL-1β, IL-6, IL-8, IL-10, MCP-1, also reactive oxygen species (ROS) and nitric oxide (NO) production by peripheral blood mononuclear cells and macrophages was demonstrated [3,7,8]. Flavonoids such as apigenin and luteolin were described as able to inhibit inflammation in central nervous system via suppression the activity/release of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), TNF-α IL-1β, IL-6, IL-31, and IL-33 produced by microglia cells [9]. However, since oral (e.g., as infusions, solutions, pellets) or topical (e.g., as creams, ointments, backfills) administration is usually recommended for most of plant extracts containing preparations, intestinal mucous and skin are the first surfaces exposed to such products.…”

Yellow Chaste Weed and Its Components, Apigenin and Galangin, Affect Proliferation and Oxidative Stress in Blue Light-Irradiated HaCaT Cells

“…Apigenin (4′,5,7-trihydroxyflavone) and galangin (3,5,7-trihydroxy flavones) are the two main flavonoids of yellow chaste weed [ 39 , 40 ]. They have been reported to possess anti-cancer, antioxidant, and anti-inflammatory properties [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Although the biological properties of apigenin and galangin have already been extensively studied, it remains unclear how they affect blue light-irradiated HaCaT cells.…”

IL-33 genetics and epigenetics in immune-related diseases

“…Apigenin and luteolin were able to suppress the production of IL-33 by inhibiting its gene and protein expression in the microglia cells. They acted mainly on MAPKs, NF-κB, and STAT3 signalling pathways in LPS-activated microglial cells [ 16 ]. Also, the chromatin remodeling protein, BRG1, possesses the ability to regulate the transcription of IL-33 in endothelial cells.…”

“…Fundamental for immune-related diseases, IL33 has a key role in controlling inflammation. On one side, Apigenin, Luteolin and immunotherapies demonstrated they efficacy in reducing the interleukin expression by acting on MAPKs, NF-κB, and STAT3 [ 16 , 25 ]. On the other side, most of the authors reported that several genes (BRG1, HDAC3, DND1, PET100, GPR160, LPAR6, SERTAD3, Rip2, NLRP3) are linked to IL-33 levels, although the exact correlation have to be clarified [ 17 – 19 , 22 , 23 ].…”